Is thrombogenesis in atrial fibrillation related to matrix metalloproteinase-1 and its inhibitor, TIMP-1?

Background and Purpose - Decreased matrix metalloproteinase-1 (MMP-1) and increased levels of its inhibitor, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), reflect impaired matrix degradation with an increase in fibrosis. A prothrombotic state has been described in atrial fibrillation (AF), increasing the risk of stroke and thromboembolism. Because structural abnormalities and remodeling of atria have been observed in AF, we hypothesized that the prothrombotic state in AF may be related to abnormal indexes of matrix degradation. Methods - We studied 48 consecutive patients ( 30 men; age, 70.5 +/- 9.0 years) with chronic nonrheumatic AF who were not on anticoagulation. Plasma levels of MMP-1, TIMP-1, and prothrombin fragment 1 + 2 ( F1 + 2, an index of thrombogenesis) were measured by enzyme-linked immunosorbent assay. M-mode, 2-dimensional, and Doppler echocardiographic studies were performed in all patients. Research indexes were compared with data from 32 control subjects in sinus rhythm who were of similar age and sex. Results - Patients with AF had lower levels of MMP-1 ( P = 0.011) but increased levels of TIMP-1 ( P = 0.033) and F1 + 2 ( P < 0.001) and a higher ratio of TIMP-1 to MMP-1 ( P = 0.009) compared with control subjects. After adjustment for sex, age, hypertension, and diabetes, TIMP-1 levels and the ratio of TIMP-1 to MMP-1 correlated with F1 + 2 levels ( r = 0.24, P = 0.038; and r = 0.26, P = 0.023, respectively). In multivariate analysis, there was no independent relationship between MMP-1, TIMP-1, or ratio of TIMP-1 to MMP-1 and the presence of AF. Conclusions - Patients with AF have evidence of impaired matrix degradation, but this was not independently associated with the presence of AF on multivariate analysis. However, an independent relationship was found between the MMP/TIMP system and prothrombotic state ( assessed by F1 + 2 levels).